Alzheimer's disease is a disease characterized by degeneration and loss of neurons as well as formation of senile plaques and neurofibrillary degeneration. Currently, Alzheimer's disease is treated only with symptomatic treatment using a symptom improving agent typified by an acetylcholinesterase inhibitor, and a fundamental remedy to inhibit progression of the disease has not yet been developed. It is necessary to develop a method for controlling the cause of the onset of pathology in order to create a fundamental remedy for Alzheimer's disease.
It is assumed that Aβ-proteins as metabolites of amyloid precursor proteins (hereinafter referred to as APP) are highly involved in degeneration and loss of neurons and onset of symptoms of dementia (see NON-PATENT DOCUMENTS 1 and 2, for example). Main molecular species of Aβ-protein are Aβ40 consisting of 40 amino acids and Aβ42 with two amino acids added at the C-terminal. The Aβ40 and Aβ42 are known to have high aggregability (see NON-PATENT DOCUMENT 3, for example) and to be main components of senile plaques (see NON-PATENT DOCUMENTS 3, 4 and 5, for example). Further, it is known that the Aβ40 and Aβ42 are increased by mutation in APP and presenilin genes which is observed in familial Alzheimer's disease (see NON-PATENT DOCUMENTS 6, 7 and 8, for example). Accordingly, a compound that reduces the production of Aβ340 and Aβ342 is expected as a progression inhibitor or prophylactic agent for Alzheimer's disease.
Aβ is produced by cleaving APP by β-secretase and subsequently by γ-secretase. For this reason, attempts have been made to create γ-secretase and β-secretase inhibitors in order to reduce Aβ production. Many of these secretase inhibitors already known are, for example, peptides and peptide mimetics such as L-685,458 (see NON-PATENT DOCUMENT 9, for example), LY-411,575 (see NON-PATENT DOCUMENTS 10, 11 and 12, for example) and LY-450,139 (see NON-PATENT DOCUMENTS 13, 14 and 15). Nonpeptidic compounds are, for example, MRK-560 (see NON-PATENT DOCUMENTS 16 and 17) and compounds having a plurality of aromatic rings as disclosed in PATENT DOCUMENT 1 and 2. However, the compound represented by the formula (VI) as disclosed in page 17 of the specification of PATENT DOCUMENT 1 differs from the compound of the present invention in that the compound is limited to a compound having a 2-aminothiazolyl group as a main structure. And the compound represented by the formula (I) as disclosed in page 6 of the specification of PATENT DOCUMENT 2 differs from the compound of the present invention in that the compound is limited to a compound having an ethynylene, an ethenylene or methine linker described as X1.